Translational Program, Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
Peritoneal Surface Malignancies Surgery Unit, Hospital Sant Joan Despí, Moises Broggi, Sant Joan Despí, Spain.
Clin Cancer Res. 2024 Sep 13;30(18):4082-4099. doi: 10.1158/1078-0432.CCR-23-4072.
Pseudomyxoma peritonei (PMP) is a rare and poorly understood malignant condition characterized by the accumulation of intra-abdominal mucin produced from peritoneal metastases. Currently, cytoreductive surgery remains the mainstay of treatment but disease recurrence and death after relapse frequently occur in patients with PMP. New therapeutic strategies are therefore urgently needed for these patients.
A total of 120 PMP samples from 50 patients were processed to generate a collection of 50 patient-derived organoid (PDO) and xenograft (PDX) models. Whole exome sequencing, immunohistochemistry analyses, and in vitro and in vivo drug efficacy studies were performed.
In this study, we have generated a collection of PMP preclinical models and identified druggable targets, including BRAFV600E, KRASG12C, and KRASG12D, that could also be detected in intra-abdominal mucin biopsies of patients with PMP using droplet digital PCR. Preclinical models preserved the histopathological markers from the original patient sample. The BRAFV600E inhibitor encorafenib reduced cell viability of BRAFV600E PMP-PDO models. Proof-of-concept in vivo experiments showed that a systemic treatment with encorafenib significantly reduced tumor growth and prolonged survival in subcutaneous and orthotopic BRAFV600E-PMP-PDX mouse models.
Our study demonstrates for the first time that systemic targeted therapies can effectively control PMP tumors. BRAF signaling pathway inhibition represents a new therapeutic opportunity for patients with BRAFV600E PMP who have a poor prognosis. Importantly, our present data and collection of preclinical models pave the way for evaluating the efficacy of other systemic targeted therapies toward extending the promise of precision oncology to patients with PMP.
假性黏液瘤（PMP）是一种罕见且尚未被充分了解的恶性疾病，其特征为腹膜转移产生的腹腔内黏液积聚。目前，细胞减灭术仍然是治疗的主要手段，但 PMP 患者在复发后经常会出现疾病复发和死亡。因此，这些患者迫切需要新的治疗策略。
对 50 名患者的 120 个 PMP 样本进行处理，生成了 50 个患者来源的类器官（PDO）和异种移植（PDX）模型的集合。进行了全外显子测序、免疫组织化学分析以及体外和体内药物疗效研究。
在这项研究中，我们生成了一组 PMP 临床前模型，并确定了可用药靶，包括 BRAFV600E、KRASG12C 和 KRASG12D，这些靶标也可以使用液滴数字 PCR 在 PMP 患者的腹腔黏液活检中检测到。临床前模型保留了原始患者样本的组织病理学标志物。BRAFV600E 抑制剂 encorafenib 降低了 BRAFV600E PMP-PDO 模型的细胞活力。体内实验的初步验证表明，全身性 encorafenib 治疗可显著抑制皮下和原位 BRAFV600E-PMP-PDX 小鼠模型中的肿瘤生长并延长生存期。
我们的研究首次证明，系统靶向治疗可有效控制 PMP 肿瘤。BRAF 信号通路抑制为预后不良的 BRAFV600E PMP 患者提供了新的治疗机会。重要的是，我们目前的数据和临床前模型集合为评估其他系统靶向治疗的疗效铺平了道路，有望将精准肿瘤学的承诺带给 PMP 患者。
